The human genome has been known for a decade, but the information provided by the genome has had only a relatively modest impact upon understanding mechanisms of disease or how mutations affect function. While the DNA sequence from a genome provides information about the linear order of the amino acid constituents of proteins, limited tools are available to understand how proteins twist and fold into their functional forms. The folded shapes of proteins determine how they function in healthy tissue, how they misfold to cause disease, and how drugs bind to proteins to modulate function.
Billions of dollars have been invested to develop instrumentation to support structural determination of biological molecules. The successes are remarkable and the results are made available online through the Protein Data Bank. Currently, the gold standard of structure determination is x-ray crystallography. However, the method requires considerable technical prowess, needs high concentrations of pure protein, and frankly depends upon a fair amount of luck. Ultimately the success of crystallography is determined by the availability of a micrometer sized defect free single crystal. This barrier has posed a tremendous limitation on the progress of biological research. For example, more than half of all proteins and 95% of integral membrane proteins do not crystallize. Thus, their structures cannot be determined by crystallography. Other alternative methods including NMR, cryoelectron microscopy, and neutron diffraction, have had limited successes. Altogether, these methods have only contributed to ˜10% of all the structures deposited in the protein data bank.